Myocardial infarction is the major cause of death in industrialized countries. Rupture of vulnerable atherosclerotic plaques is currently recognized as an important mechanism for acute myocardial infarction, which often results in sudden death. Recent advances in cardiovascular research have identified anatomic, biomechanical, and molecular features of atherosclerotic plaques that predispose them to rupture. In a majority of vulnerable plaques, these features include 1) the presence of activated macrophages at the shoulder or edge of the plaque, 2) a thin fibrous cap (<60 μm) and 3) a large lipid pool. The lipid pool is thought to apply force to the fibrous cap that causes it to become compromised. Once it is ruptured, the lipid enters the vessel lumen, causing thrombosis, arterial occlusion, myocardial ischemia, and infarction. In addition to lipid-rich plaques with a thin fibrous cap, other plaque types have been recently implicated as vulnerable plaques. These plaques contain a surface erosion where the intima has been denuded, leaving a rough surface at risk for causing platelet aggregation and acute thrombosis.
Coronary arteries that do not contain plaque have a layered structure consisting of an intima, media, and adventitia. A simple model of a lipid-rich plaque is a two layered structure consisting of a fibrous cap and an underlying lipid pool. Other atherosclerotic plaque types consist of one layer, either fibrous or calcified. Research indicates that the distinct layers present in atherosclerotic plaques have different scattering, absorption, and anisotropy coefficients. It is believed that the measurement of these parameters using light will enable characterization of plaque type in vivo and allow for the diagnosis of vulnerable plaques.
Cellularity of fibrous caps of atherosclerotic plaque, manifested by the infiltration of macrophages (average size 20-50 μm), is thought to weaken the structural integrity of the cap and predispose plaques to rupture. Macrophages, and other plaque related cells, produce proteolytic enzymes such as matrix metalloproteinases that digest extracellular matrix and compromise the integrity of the fibrous cap. Activated macrophages are strongly colocalized with local thrombi in patients who have died of acute myocardial infarction and are more frequently demonstrated in coronary artery specimens obtained from patients suffering from acute coronary syndromes compared with patients with stable angina. This evidence suggests that an imaging technology capable of identifying macrophages in patients would provide valuable information for assessing the likelihood of plaque rupture. Results from intracoronary OCT, recently performed in patients, have shown an improved capability for characterizing plaque microstructure compared with IVUS. To date, however, the use of OCT for characterizing the cellular constituents of fibrous caps has not been fully investigated.
It would be desirable to have a means for using remitted light to measure the optical properties of atherosclerotic plaques, determine plaque cap thickness or identify plaques with surface erosions and as a result assess coronary plaque vulnerability.
A method that detects plaques vulnerable to rupture could become a valuable tool for guiding management of patients at risk and may ultimately prevent acute events. Many different catheter-based methods are under investigation for the detection of vulnerable plaques. These methods include intravascular ultrasound (IVUS), optical coherence tomography (OCT), fluorescence spectroscopy, and infrared spectroscopy. While IVUS and OCT are used to obtain cross-sectional images of tissue, only OCT has been shown to have sufficient resolution to detect the presence of a thin fibrous cap. Fluorescence and infrared spectroscopy are methods that primarily detect the presence of lipids within the vessel wall. Of the four proposed techniques, only OCT has been shown to be capable of spatially resolving parameters directly responsible for plaque rupture.
Background Principles
The backreflected light scattered from within a turbid medium, such as tissue, is affected by the optical properties of the medium. The optical properties that determine the propagation of light in tissue are the absorption coefficient, μa, the scattering coefficient, μs and the total attenuation coefficient, μt, whereμtμs+μa The absorption coefficient is linearly related to the concentration of the absorber, such thatμa=ε[Ab]where ε is the molar extinction coefficient for the absorber and [Ab] is the molar concentration of the absorber.
Often, the mean cosine of the scattering phase function, g, is combined with μs to form the transport scattering coefficient:μ′s=μs(1−g)
Propagation of light described using the transport scattering coefficient can be considered isotropic since the scattering coefficient has been normalized by the anisotropy coefficient, g.
Propagation of light within multiply scattering media is described by the radiative transport equation. Solutions to the radiative transport equation by use of diffusion theory approximations have allowed the use of remitted light to predict the optical properties of homogeneous highly scattering media. Application of these techniques for diagnosing neoplasia has been problematic, however, due to tissue inhomogeneities and the large depth of tissue which must be probed to identify small tumors deeply embedded in tissue. Nevertheless, in the limited setting of atherosclerotic plaques, the tissue structure is less heterogeneous and the pathology is at the surface of the vessel. These two features of arterial pathology make characterization of atherosclerotic plaques by measurement of optical properties possible.
FIGS. 1A and 1B show a schematic of the spatial remittance (r) for a fibrous plaque (FIG. 1A) and a lipid-rich plaque with a fibrous cap (FIG. 1B). The different optical properties of the two layers gives rise to a distinct remittance profile. This profile can be measured and the optical properties and thicknesses of the layers can be determined using two-layer diffusion approximation to the radiative transport equation. In FIGS. 1A and 1B, a single beam of light is incident on the sample which is depicted as a two-layer model. Diffusion of light through the media produces a spatial remittance profile that is dependent on the optical properties of the media (FIG. 1A). In FIG. 1B, i.e., the three-dimensional optical fluence is depicted as iso-contours. As can be seen in this simple schematic, the additional layer effects the spatially dependent three dimensional fluence and the remittance profile at the surface of the model. This effect is dependent on the optical properties and thicknesses of the layers and represents one method for measuring optical properties to characterize plaque composition and cap thickness. FIG. 2 shows the results of a preliminary study performed demonstrating the difference in radial remittance for different plaque types, in which Gaussian fits of the spatial remittance profiles were measured from a normal aorta and two lipid-rich plaques, one containing a thick fibrous cap and the other, a thin fibrous cap. The trend towards decreasing remittance distribution width is a result of a decrease in the amount of light scattered from the fibrous cap (λ=633 nm).